Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study.

PURPOSE: Immune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC. METHODS: We analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003). RESULTS: A total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046). CONCLUSION: ICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.

The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear. METHODS: We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model. RESULTS: A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ≥50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ≥50% was more significant than that in the entire cohort. CONCLUSIONS: Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression <50%.

Impact of previous thoracsic radiation therapy on the efficacy of immune checkpoint inhibitors in advanced non-smasll-cell lung cancer.

OBJECTIVES: Studies investigating the association between radiation therapy and the efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer have provided inconsistent results, likely due to relatively small cohort sizes. This study investigated the effect of previous thoracic radiation therapy on the efficacy of immune checkpoint inhibitor therapy in a large non-small-cell lung cancer cohort. PATIENTS AND METHODS: We conducted a retrospective cohort study using data from 531 non-small-cell lung cancer patients who received monotherapy with programmed cell death protein 1/programmed death-ligand 1 inhibitors at nine institutions. The effects of thoracic radiation therapy on the efficacy of immune checkpoint inhibitors were investigated. RESULTS: A total of 531 non-small-cell lung cancer patients treated with immune checkpoint inhibitors were included in this study. The progression-free survival period was significantly longer in patients that had received thoracic radiation therapy before immune checkpoint inhibitor therapy compared to those without previous thoracic radiation therapy (median progression-free survival 5.0 vs. 3.0 months, P = 0.0013). A multivariate analysis showed that thoracic radiation therapy was an independent predictive factor of improved progression-free survival (hazard ratio of progression-free survival: 0.79, P = 0.049). In contrast, extra-thoracic radiation therapy was associated with inferior outcomes (median progression-free survival 3.0 vs. 4.2 months, P = 0.0008). CONCLUSION: Previous thoracic radiation therapy, but not prior extra-thoracic radiation therapy, enhanced the efficacy of anti-programmed cell death protein 1/programmed death-ligand 1 therapy in non-small-cell lung cancer patients.

Characteristics of patients with EGFR-mutant non-small-cell lung cancer who benefited from immune checkpoint inhibitors.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are less effective in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, a small percentage of patients with EGFR-mutant NSCLC do respond, and the characteristics of these patients are not known. Here, we identify the characteristics of patients who may respond to ICI therapy for EGFR-mutant NSCLC. PATIENTS AND METHODS: The medical records of NSCLC patients with EGFR mutations who received PD-1/PD-L1 antibody monotherapy at nine institutions were reviewed. RESULTS: In total, 58 patients with EGFR-mutant NSCLC were analyzed. Various clinical factors such as smoking history and EGFR mutation type were not associated with progression-free survival (PFS) of ICIs, while the PFS of prior EGFR tyrosine kinase inhibitors (TKIs) was inversely associated with that of ICIs. Patients who responded to prior EGFR TKIs for > 10 months exhibited a significantly shorter response to ICIs compared to those who had responded for ≤ 10 months (PFS of ICI: 1.6 vs. 1.9 months; hazard ratio: 2.54; 95% confidence interval 1.26-5.12; p = 0.009). However, patients who responded to ICIs for > 6 months responded to prior EGFR TKIs for significantly shorter periods compared to those who responded to ICIs for ≤ 6 months (PFS of prior EGFR TKI: 5.3 vs. 12.1 months; log-rank test: p = 0.0025). CONCLUSION: The duration of response to prior EGFR TKIs could be a predictive marker of ICI therapy in EGFR-mutant NSCLC patients.

A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cancers Harboring HER2 Aberration in Japan (HER2-CS STUDY).

BACKGROUND: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. METHODS: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. RESULTS: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. CONCLUSIONS: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. TRIAL REGISTRY: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691.

A phase II trial of EGFR-TKI readministration with afatinib in advanced non-small-cell lung cancer harboring a sensitive non-T790M EGFR mutation: Okayama Lung Cancer Study Group trial 1403.

PURPOSE: The aim of this study was to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration using afatinib in patients with non-small-cell lung cancer (NSCLC) with a sensitive non-T790M EGFR mutation who had received cytotoxic chemotherapy after acquiring resistance to EGFR-TKIs. METHODS: Eligible patients had EGFR-mutant tumors resistant to first- or second-generation EGFR-TKIs and an EGFR-TKI-free period with cytotoxic agents. Confirmation of absence of the T790M mutation was required before registration. Afatinib (40 mg/body) was administered daily. The primary endpoint was progression-free survival (PFS). We assumed estimated and threshold PFS times of 3.3 and 1 months, with an α of 0.05 and ß of 0.1, respectively. RESULTS: Twelve patients were enrolled from December 2014 to May 2017. The objective response rate and disease control rate were 17% and 84%, respectively. The median PFS time was 4.2 months (95% confidence interval [CI] 2.0-5.8), which met the pre-defined primary endpoint. The median overall survival was 11.6 months (95% CI 9.2-not reached). Grade 3 or worse adverse events included diarrhea (25%), elevated creatinine levels (8%), and hypokalemia (8%), without any treatment-related deaths. CONCLUSION: EGFR-TKI readministration with afatinib for sensitive EGFR-mutant NSCLC without T790M after resistance to a first- or second-generation EGFR-TKI yielded modest activity with tolerable toxicity. It might be one of the treatment options in patients who do not possess T790M tumors, although further studies in this patient setting are warranted.

Three-Arm Randomized Trial of Sodium Alginate for Preventing Radiation-Induced Esophagitis in Locally Advanced Non-Small Cell Lung Cancer Receiving Concurrent Chemoradiotherapy: The OLCSG1401 Study Protocol.

Concurrent chemoradiotherapy (CRT) is the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, this intensive therapy often causes severe esophagitis, which could deteriorate a patient's quality of life (QOL), leading to poor treatment compliance. Sodium alginate, approved in Japan for gastritis, is sufficiently highly viscous to remain in the esophageal mucosa, providing a protective effect in the esophagus. To investigate whether this compound has a preventive effect against severe esophagitis in patients receiving concurrent CRT, we plan a 3-arm randomized trial of sodium alginate with 2 different schedules versus water. The primary endpoint is set as the proportion of patients with grade ≥ 3 esophagitis using the Common Terminology Criteria for Adverse Events, version 4.0. With stratification by institute, performance status, and percentage of the esophageal volume receiving >35 Gy, the patients will be randomly assigned to 1 of the following groups: sodium alginate initiated concomitantly with CRT (group A), sodium alginate initiated soon after the development of extremely mild esophagitis during CRT (group B), or water administered throughout CRT (group C). Assuming that the proportion of grade ≥ 3 esophagitis would be 8% in groups A and B and 27% in group C, the required sample size would be 200 patients, with 70% power and 5% α. The secondary endpoints include QOL, the frequency of additional prescriptions of analgesics, treatment response, and survival. The results of the present study will clarify whether sodium alginate can prevent esophagitis in patients with LA-NSCLC undergoing CRT.

Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy for patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression-free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR-TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR-TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression-free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial.

A phase II study of topotecan and cisplatin with sequential thoracic radiotherapy in elderly patients with small-cell lung cancer: Okayama Lung Cancer Study Group 0102.

PURPOSE: The treatment outcome in elderly patients with limited-disease small-cell lung cancer (LD-SCLC) remains poor. We carried out a phase II trial of split topotecan and cisplatin (TP) therapy and sequential thoracic radiotherapy for elderly LD-SCLC patients as a follow-up to our previous phase I trial. METHODS: In total, 30 patients aged 76 years or older, with untreated LD-SCLC were enrolled. Four courses of topotecan (1.0 mg/m(2), days 1-3) and cisplatin (20 mg/m(2), days 1-3) were administered, followed by thoracic radiotherapy (1.8 Gy/day, total of 45 Gy). The primary end point was the overall response rate (ORR). RESULTS: The trial was terminated early with 22 patients because of slow accrual. Their median age was 79 years. The median number of courses of chemotherapy administered was three, and the actual completion rate of the entire treatment course was 41 %. The ORR was 68 % with a 95 % confidence interval of 47-89 % (15/22 cases). The median progression-free survival and overall survival were 9.1 and 22.2 months, respectively. The main toxicity was myelosuppression, with grades 3-4 neutropenia (96 %), thrombocytopenia (50 %), and febrile neutropenia (32 %). CONCLUSIONS: This regimen produced a favorable survival outcome, despite moderate-to-severe toxicity profiles. Further efforts are necessary to define an optimal regimen for elderly patients with limited SCLC.

Protocol Design for the Bench to Bed Trial in Alectinib-Refractory Non-Small-Cell Lung Cancer Patients Harboring the EML4-ALK Fusion Gene (ALRIGHT/OLCSG1405).

Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory non-small-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with non-small-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided α of 0.05, ß of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK+ non-small-cell lung cancer even in the alectinib-refractory setting.

Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are now key agents in treating EGFR-mutant non-small cell lung cancer (NSCLC). The efficacy of gefitinib or erlotinib monotherapy can be predicted by the development of a skin rash. However, it has not been fully evaluated if this is the case with afatinib monotherapy. METHODS: We retrospectively studied 49 consecutive patients with EGFR-mutant NSCLC who received afatinib therapy between 2009 and 2015. The relationship of several toxicities with tumor response was examined. RESULTS: Grade 2, or more severe, common adverse events (AEs) included skin rash in 17 patients (35 %), diarrhea in 19 (39 %) and mucositis in 15 (31 %). Of these, the number of patients who developed ≥Grade 2 AEs during the first week after the initiation of afatinib therapy was: five patients had skin rash (10 %), 12 patients had diarrhea (25 %) and four patients had mucositis (8 %). As for an objective response, 21 (43 %) of the 49 had a partial response. Associating the AEs with the antitumor effect, those who had a ≥Grade 2 skin rash within the first week tended to have a greater tumor response compared with those without a rash (80 vs. 39 %; p = 0.077). CONCLUSION: Our small study demonstrated that the early development of a skin rash might be associated with the response to afatinib monotherapy.

[HER2-Positive Advanced Gastric Cancer with Disseminated Intravascular Coagulation and Diffuse Bone Marrow Carcinomatosis Successfully Treated with S-1/Trastuzumab Chemotherapy--A Case Report].

Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2), has been proven to result in a survival benefit for the treatment of patients with HER2-positive advanced gastric cancer (AGC). However, data are lacking for the treatment of those with disseminated intravascular coagulation (DIC) and diffuse bone marrow carcinomatosis. A 77-year-old woman presented with back pain and fatigue since 2 months. Esophagogastroduodenoscopy showed a scirrhous lesion in the gastric corpus, which was biopsied and identified as signet-ring cell carcinoma with HER2 overexpression on immunohistochemistry. Laboratory testing, bone scintigraphy, and bone marrow biopsy were conducted, and she was diagnosed with HER2-positive AGC with DIC and diffuse bone marrow carcinomatosis. She underwent chemotherapy with the following regimen: oral administration of 80 mg/m2 S-1 for 2 weeks and 6 mg/kg trastuzumab infusion on day 6 every 3 weeks, which significantly improved the DIC. She was discharged from the hospital 73 days after admission and survived for 438 days after diagnosis. To the best of our knowledge, this is the first case report in which HER2-positive AGC complicated by DIC with diffuse bone marrow carcinomatosis was successfully treated with combined chemotherapy consisting of S-1 plus trastuzumab.

A phase II study of cisplatin plus S-1 with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0501.

BACKGROUND: Although cisplatin-based chemotherapy combined with thoracic irradiation (TRT) is a standard treatment for unresectable, locally advanced non-small cell lung cancer (NSCLC), this treatment outcome has remained unsatisfactory. We had previously conducted a phase I trial of cisplatin plus S-1, an oral 5-fluorouracil derivative, and TRT, which were safe and effective. METHODS: In this phase II trial, 48 patients with stage III NSCLC received cisplatin (40mg/m(2) on days 1, 8, 29 and 36) and S-1 (80mg/m(2) on days 1-14 and 29-42) and TRT (60Gy). The primary endpoint was the response rate. RESULTS: A partial response was observed in 37 patients (77%; 95% confidence interval: 63-88%). At a median follow up of 54 months, the median progression-free survival and median survival time were 9.3 and 31.3 months, respectively. No difference in efficacy was observed when the patients were stratified by histology. Toxicities were generally mild except for grade 3 or worse febrile neutropenia and pneumonitis of 8% and 4%, respectively. No patient developed severe esophagitis. At the time of this analysis, 35 (73%) of the 48 patients recurred; 15 (31%) showed distant metastasis, 17 (35%) had loco-regional disease, and 2 (4%) showed both loco-regional disease and distant metastasis. CONCLUSIONS: This chemoradiotherapy regimen yielded a relatively favorable efficacy with mild toxicities in patients with locally advanced NSCLC.

A phase II study of S-1 chemotherapy with concurrent thoracic radiotherapy in elderly patients with locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0801.

BACKGROUND: Although thoracic irradiation (TRT) is a standard treatment for elderly patients with locally advanced non-small-cell lung cancer (LA-NSCLC), treatment outcomes are poor. We previously reported a phase I trial combining S-1, an oral 5-fluorouracil derivative, and thoracic radiation, which yielded safe and effective outcomes. METHODS: In this phase II trial, 30 patients aged 76 years or older with LA-NSCLC received S-1 (80 mg/m(2) on days 1-14 and 29-42) and TRT (60Gy). The primary end-point was the response rate. RESULTS: The median age and pre-treatment Charlson score were 79 years and 1, respectively. The mean proportions of the actual doses of S-1 and TRT delivered relative to the planned doses were 95% and 98%, respectively. Partial responses were observed in 19 patients (63%; 95% confidence interval: 45-82%), which did not attain the end-point. At a median follow-up time of 23.7 months, the median progression-free survival and median survival times were 13.0 months and 27.9 months, respectively. No difference in efficacy was observed upon stratification by tumour histology. Toxicities were generally mild, except for grade 3 or greater febrile neutropenia and pneumonitis in 7% and 10% of patients, respectively. No patient developed severe oesophagitis. CONCLUSIONS: Although the primary end-point was not met, concurrent S-1 chemotherapy and radiotherapy yielded favourable survival data. Also, the combined treatment was well-tolerated in elderly patients with LA-NSCLC.

[A case of advanced gastric cancer with multiple bone metastases and disseminated intravascular coagulation successfully treated by combination chemotherapy of S-1 plus docetaxel].

Advanced gastric cancer (AGC) accompanied by disseminated intravascular coagulation(DIC)has a poor prognosis, and has no established therapy. Here, we report a case of a 69-year-old woman referred to our hospital due to severe anemia and thrombocytopenia. Esophagogastroduodenoscopy demonstrated an AGC in the cardiac part of the stomach, which was histologically diagnosed as poorly-differentiated adenocarcinoma. Bone scintigraphy showed multiple metastases to the bone marrow. Her diagnosis was DIC resulting from AGC, with multiple bone metastases. She underwent chemotherapy with the following regimen: 60mg/m2 docetaxel(DOC)infusion on day 1 and daily oral administration of 100 mg/m2 S-1 for two weeks every three weeks. DIC subsided rapidly after initiation of the therapy and resolved in 12 days. She was discharged from the hospital 56 days after admission and survived 303 days. To our knowledge, this is the first case of AGC reported in the Japanese and English literature to obtain long-term survival in this setting. Combined chemotherapy of S-1 plus DOC may play an important role in the treatment of AGC developing DIC.

A phase II study of amrubicin and topotecan combination therapy in patients with relapsed or extensive-disease small-cell lung cancer: Okayama Lung Cancer Study Group Trial 0401.

BACKGROUNDS: Chemotherapy is a mainstay in the treatment of extensive-disease small-cell lung cancer (ED-SCLC), although the survival benefit remains modest. We conducted a phase II trial of amrubicin (a topoisomerase II inhibitor) and topotecan (a topoisomerase I inhibitor) in chemotherapy-naïve and relapsed SCLC patients. METHODS: Amrubicin (35 mg/m(2)) and topotecan (0.75 mg/m(2)) were administered on days 3-5 and 1-5, respectively. The objective response rate (ORR) was set as the primary endpoint, which was assessed separately in chemotherapy-naïve and relapsed cases. RESULTS: Fifty-nine patients were enrolled (chemotherapy-naïve 31, relapsed 28). The ORRs were 74% and 43% in the chemotherapy-naïve and relapsed cases, respectively. Survival data were also promising, with a median progression-free survival time and median survival time of 5.3 and 14.9 months and 4.7 and 10.2 months in the chemotherapy-naïve and relapsed cases, respectively. Even refractory-relapsed cases responded to the treatment favorably (27% ORR). The primary toxicity was myelosuppression with grades 3 or 4 neutropenia in 97% of the patients, which led to grades 3 or 4 febrile neutropenia in 41% of the patients and two toxic deaths. CONCLUSION: This phase II study showed the favorable efficacy and moderate safety profiles of a topotecan and amrubicin two-drug combination especially in relapsed patients with ED-SCLC.

A phase I study of S-1 with concurrent thoracic radiotherapy in elderly patients with localized advanced non-small cell lung cancer.

S-1, an oral 5-fluorouracil derivative, is effective against advanced non-small cell lung cancer (NSCLC) with mild toxicity and synergistic effects with radiation in preclinical trials. In this phase I study, we evaluated the dose-limiting toxicity and recommended dose of S-1 for a future phase II study when administered concurrently with thoracic radiation (total dose of 60 Gy at 2 Gy per daily fraction) in elderly patients (>75 years old) with localized advanced NSCLC. S-1 was administered on days 1-14 and 29-42 at the following dosages: 60, 70, and 80 mg/m(2)/day. Twenty-two previously untreated patients were enrolled in this study. Dose-limiting toxicity included febrile neutropenia, thrombocytopenia, stomatitis, and pneumonitis. One patient had grade 5 radiation pneumonitis. No other patient experienced radiation pneumonitis or esophagitis exceeding grade 2. The recommended dose for S-1 was determined to be 80 mg/m(2)/day, which produced an overall response rate of 75% (n=12). The median progression-free survival time was 11.5 months (95% confidence interval: 7.1-15.8 months) with a median follow-up time of 27.9 months. These results indicate that concurrent treatment with S-1 and thoracic radiation is a feasible option for NSCLC in the elderly. A phase II study is currently under way.

Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007.

PURPOSE: To demonstrate the efficacy of docetaxel and cisplatin (DP) chemotherapy with concurrent thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS: Patients age 75 years or younger with LA-NSCLC, stratified by performance status, stage, and institution, were randomly assigned to two arms consisting of DP (docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2) on days 1, 8, 29, and 36) or mitomycin, vindesine, and cisplatin (MVP) chemotherapy with concurrent TRT. RESULTS: Between July 2000 and July 2005, 200 patients were allocated into either the DP or MVP arm. The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted log-rank as an unplanned analysis). There was a trend toward improved response rate, 2-year survival rate, median progression-free time, and median survival in the DP arm (78.8%, 60.3%,13.4 months, and 26.8 months, respectively) compared with the MVP arm (70.3%, 48.1%, 10.5 months, and 23.7 months, respectively), which was not statistically significant (P > .05). Grade 3 febrile neutropenia occurred more often in the MVP arm than in the DP arm (39% v 22%, respectively; P = .012), and grade 3 to 4 radiation esophagitis was likely to be more common in the DP arm than in the MVP arm (14% v 6%, P = .056). CONCLUSION: DP chemotherapy combined with concurrent TRT is an alternative to MVP chemotherapy for patients with LA-NSCLC.